1. Field of Invention
This invention relates to derivatives of 2,6-dioxopiperidine, also known as glutarimide, their preparation and pharmaceutical compositions containing them.
2. Description of Prior Art
U.S. Pat. No. 2,673,205 (Ciba) claims 3,3-disubstituted-glutarimides of formula ##STR2## R.sup.1 represents an aliphatic hydrocarbyl group of 1 to 6 carbon atoms and Ar represents a phenyl or pyridyl group, and R.sup.2 represents hydrogen or a substituent group such as alkyl, acyl, phenyl or benzyl. 12 such compounds were prepared, 11 of them being 3-phenyl derivatives (Ar in formula 1=phenyl) and 3-ethyl-3-(3-pyridyl)glutarimide of formula ##STR3## where Et=ethyl. The class of compounds claimed in U.S. Pat. No. 2,673,205 is stated to have an anti-convulsive effect. However, the preferred compound, 3-ethyl-3-phenylglutarimide was subsequently marketed as the sedative and hypnotic agent glutethimide. The later U.S. Pat. No. 2,848,455 (Ciba) claims 3-methyl and -ethyl-3-(4-aminophenyl)glutarimides as anti-convulsive agents. The 3-ethyl compound is known as aminoglutethimide. V. Carelli, Ann. Chim. (Rome) 51, 713-718 (1961), describes "Nota", 3-ethyl-3-(2-pyridyl)-glutarimide, as having a sedative and hypnotic effect. U.S. Pat. No. 3,057,867 claims a large class of N-aminoglutarimides having sedative and anti-convulsive activity.
The present invention is concerned with an entirely different field of therapy, namely anti-cancer therapy, specifically the treatment of oestrogen-dependent tumors. Such tumors are most commonly produced in the breast tissue of female mammals. Within the last 5 years or so aminoglutethimide has come seriously into the reckoning for treatment of advanced breast cancer in post-menopausal patients. Its advantages over tamoxifen have been set out in a recent paper by I. E. Smith et al., British Medical Journal, 283, 1432-1434 (1981). One important factor in the success of aminoglutethimide in this connection is its ability to inhibit in vivo the activity of the enzyme aromatase in peripheral tissue. This enzyme is required for the conversion of androgens into oestrogens. Aminogluthethimide therefore breaks the metabolic pathway to oestrogens. Unfortunately, however, aminoglutethimide also inhibits the enzyme desmolase which is required for the metabolic conversion of cholesterol to corticosteroids. Since the body needs corticosteroids, treatment with aminoglutethimide has to be supplemented by cortisone replacement therapy. Furthermore, depletion of corticosteroids causes a reflex rise in adrenocorticotrophic hormone (ACTH) which stimulates the conversion of cholesterol to pregnenolone by the enzyme desmolase and consequently the production of oestrogen precursors.